Team uses equipment leasing to stretch funds

Dr. Kassem Ashe (KA), Cardiovascular Surgeon at St. Mary’s General Hospital in Kitchener, Ontario, Canada, and Duane Cronin (DC), Professor of Mechanical and Mechatronics Engineering at University of Waterloo, recently leased a ViVitro Pulse Duplicator for early design work in their Autologous Pericardial Tissue valve project. ViVitro Lab Manager Rob Fraser (RA) spoke with them recently about the project, their experience leasing the equipment, and future plans.

RF: Please tell us about the work you are doing.

DC: We’re looking at a version of an aortic heart valve that can be created from autologous pericardium. Our goals were to understand the effects of changes in dimension on the functionality and performance of the valve, and ultimately to optimize the geometry of the valve.

KA: In terms of background, the limitations of using biological aortic valves with respect to durability are well known. The issues relate to early calcification, accessibility, and cost. We have seen early failures in patients–in non high risk patients, meaning no renal failure, no calcium drugs for osteoporosis, not a young patient– and we have to explant these valves because they have failed.

We are looking to solve this issue with autologous pericardium. To date most attempts to use autologous pericardium have been to reconstruct the valve free hand, (Duran, Osaki). Autologous pericardium is much more durable and resists calcification when compared with bovine or porcine pericardium. Despite the anti-calcification modalities developed and used today there still is a propensity to early calcification in many subgroups, namely the young patient, renal failure. We are also looking at an ideal valve design. The idea is that a valve could be fashioned as soon as the patient’s chest was opened and before the patient was put on pump. We started off with something that was going to be created by hand (stentless) and we moved to a valve that is stented with design features that potentially are superior to existing valves on the market. We are at the stage of fine tuning our computer modelling with the aim of creating a prototype that we can mold or 3D print and then have something that can be easily put in by the majority of surgeons.

We’re utilizing both experimental and computational methods to understand the challenges and functionality of these valves in order to optimize them. We’re taking a new and different approach in terms of construction and materials in order to address the well-known challenges, including calcification and durability, which exist today.

RF: Calcification is certainly an issue everyone is looking to resolve. How is the work going?

KA: We leased the pulse duplicator back in August and we had a number of technical difficulties, not so much in the case of the Pulse Duplicator—it worked perfectly. We had some initial ideas in terms of the concept of the valve we were going to use and then we had some difficulty implementing it and getting consistent numbers. We were implanting a free hand sewn valve into a Valsalva graft. The issue related to significant leakage through multiple needle holes that significantly affected closing volume. Towards the end of our two month rental with ViVitro, we were able to generate a number of great results that at least matched or could be superior to existing valves in terms of hemodynamics. We’re at the stage of completing the computational model that Duane is working on, and then, hopefully, we will revise the design further and get some more funding so we can take it further.

DC: We’ve been working in experimental and computational modelling for many years and found that the fusion of those two areas has enabled us to answer a lot of challenging questions. We know that for something as critical as a heart valve, we can’t just live in the computational world. There has to be some real physical testing and prototypes to understand what’s going on in order to use and even to validate these models. However, as a starting point the models can give us some insight into the effective geometric variations, without material and other variabilities that may creep into experimental testing. Each aspect of this initial phase of work had a benefit in terms of the modelling giving us really good insights into the physics, what we wanted to achieve and how we could choose an optimization path. And then on the physical side, being able to actually test the valves themselves in a realistic condition and understand how these effects were supplemented by real world aspects as well.

RF: What challenges have you faced with this project?

KA: We spent a considerable amount of time getting ethics approval to use human tissue. Unlike using porcine and bovine tissue that are readily available and don’t need the same hurdles, we had to get ethics approval to use live human pericardium. We now have ethics approval to test our various designs.

RF: What is next for this project?

DC: There are still many technical challenges to solve in this space. We think we’re on the right path moving forward. We have good potential for success by identifying what are the critical areas. Without focusing on the other valves that are out there today, we know that there are some good valves and some that are having some challenges and have a solid plan to address those challenges.

ViVitro has been very understanding and helpful in terms of allowing us to achieve some very significant goals in a very, very short period of time– which was the intent of our initial funding. Our goal now is to secure additional funding to continue our studies.

KA: What started off as research project, has now expanded on to something entrepreneurial.

Because of some of the travels I’ve done, I have seen firsthand that the developing world requires an ideal tissue valve. If you look at the world at large, there is an incredible population that requires these valves because rheumatic heart disease and congenital valvular disease continue to be endemic in these third world countries. These people need a valve that doesn’t require any anti-coagulation because they are going back into their tribes or communities, and due to the distance, follow-up is limited. The practice has been primarily to put in the tissue valve of choice, the people go back into their community and they are lost to follow up. Unfortunately, they go on to early valve failure from calcification.

Another problem with tissue valves is shortage of heart valves in certain sizes. That’s because emerging markets have created such a demand that we’re seeing these shortages. So there is need to have an alternative material with potentially better durability.

RF: You mentioned the lack of available valve sizes. Is this the smaller sizes that don’t fit the North American population norms?

KA: Surprisingly, it’s primarily the most popular sizes, the 23-25 mm size valves are very hard to get now. We’re back ordered because we’re using them so much. We have the same problem with grafts. Having said that, when the market leader is having problems meeting the expanding market demands (primarily it’s the Asian market), companies that are not the market leaders are now seeing this incredible window to come in. Unfortunately, I think that some of the valve designs that exist with these other competitors may not be ideal. Without mentioning names, there’s a company that we’ve implanted a significant number of valves that we are seeing coming back today. I am also old enough to remember the Ionescu Shiley valve and early failure, because of a design flaw. Today’s generation of tissue valves are not ideal. I think the very fact that when I open up the ViVitro website and you are advertising a device/methodology to measure calcification extent and location to effect design speaks to the fact that there have been hundreds of millions of dollars invested to look at anti-calcification methods and to date nobody has solved that problem yet. We believe with autologous pericardium and looking at a different type of design that can be fashioned quickly and with the engineering expertise that Duane brings to the table, hopefully we will be able to fill that void.

RF: Any advice for readers?

KA: Persistence and get a great team partner like Duane. Collaborate and persistence. And when you fail, collaborate and continue persisting.

DC: Our rule of thumb is: “Experimental testing always takes longer than you plan for”. It’s just the nature of experimentation. I’ve been doing it for a number of years and it’s always that way. Take a nice progressive and step-wise approach to development. Start with something you know and then evolve or gradually evolve towards your intended design. I think that’s a classical experimental mechanical approach that always serves well in these complex environments like a heart valve.

RF: I was laughing to myself when you said that experiments always take longer than you think.

DC: I always tell my graduate students to use the rule of Pi. If you budget 2 hours, multiple it by Pi and that’s how long it will take you. I used to say 3-4X, but engineers always believe a formula if there is Pi in it.